title: Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.
abstract: BACKGROUND
  We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients.
  
  
  METHODS
  For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population.
  
  
  RESULTS
  Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p<0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (<1%) in the combination group; p=0·185).
  
  
  CONCLUSIONS
  Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada. Electronic address: andre.robidoux.chum@ssss.gouv.qc.ca.
authors.forename: André
authors.initials: A
authors.lastname: Robidoux
authors.forename: Gong
authors.initials: G
authors.lastname: Tang
authors.forename: Priya
authors.initials: P
authors.lastname: Rastogi
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Azar
authors.forename: James N
authors.initials: JN
authors.lastname: Atkins
authors.forename: Louis
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.forename: Louis
authors.initials: L
authors.lastname: Baez-Diaz
authors.forename: Shakir
authors.initials: S
authors.lastname: Sarwar
authors.forename: Richard G
authors.initials: RG
authors.lastname: Margolese
authors.forename: William B
authors.initials: WB
authors.lastname: Farrar
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brufsky
authors.forename: Henry R
authors.initials: HR
authors.lastname: Shibata
authors.forename: Hanna
authors.initials: H
authors.lastname: Bandos
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Costantino
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Mamounas
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D002170:Canada; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D000077341:Lapatinib; D016015:Logistic Models; D008408:Mastectomy; D058990:Molecular Targeted Therapy; D020360:Neoadjuvant Therapy; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011647:Puerto Rico; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D014481:United States
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D000077341:Lapatinib; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human